tbuckley/cabot-search huggingface dataset:
P941: SAFETY AND CLINICAL ACTIVITY OF BELANTAMAB MAFODOTIN WITH LENALIDOMIDE PLUS DEXAMETHASONE IN PATIENTS WITH RELAPSED/REFRACTORY MULTIPLE MYELOMA (RRMM): DREAMM-6 ARM-A INTERIM ANALYSIS
Authors: H. Quach, M. Gironella, C. Lee, R. Popat, P. Cannell, R. S. Kasinathan, B. Chopra, R. Rogers, G. Ferron-Brady, S. Shafi-Harji, N. Patel, J. Opalinska, I. Gupta, B. Augustson
Journal: HemaSphere (2022)

Background: Belantamab mafodotin (belamaf; BLENREP) is a B-cell maturation antigen-targeting antibody–drug conjugate approved for patients with RRMM as monotherapy at 2.5 mg/kg Q3W. Preclinical data demonstrate synergy between belamaf and lenalidomide (Len), suggesting added benefit when combined with standard of care such as Len + dexamethasone (Dex). Aims: DREAMM-6 (NCT03544281) Arm A is evaluating belamaf in combination with LenDex in patients with RRMM. Methods: This ongoing, two-part, two-arm, open-label study included patients with RMMM previously treated with ≥1 line of therapy (LOT). Patients received 4 belamaf doses/schedules (1.9 mg/kg Q8W or Q4W; 2.5 mg/kg Q4W or Q4W SPLIT dose [50% on Days (D)1, 8] IV) in combination with Len (20 mg PO D1–21) and Dex (20 mg PO/IV D1, 8, 15, 22). Primary objectives were safety (including treatment-related [TR]AEs related to the combination belamaf and LenDex), tolerability, and efficacy (including overall response rate [ORR] defined as ≥partial response). Results: As of this interim analysis (data cut: July 23, 2021), 45 patients received ≥1 dose (12 at 1.9 mg/kg Q8W; 4 at 1.9 mg/kg Q4W; 16 at 2.5 mg/kg Q4W; 13 at 2.5 mg/kg Q4W SPLIT). Across cohorts, the median age was 68 years (range: 36–80). Thirteen patients (29%) had high-risk cytogenetics and 6 (13%) had extramedullary disease. Median prior LOT was 3 (range: 1–11) and 26 (58%) had prior Len treatment. The median duration of follow-up and ORR ranged across cohorts (Table). The median duration of response was only reached in the 1.9 mg/kg Q4W cohort (11.1 mo [95% CI: 3.7–not reached [NR]). At the time of data cut, median progression-free survival was not reached in the 1.9 mg/kg Q8W or 2.5 mg/kg Q4W cohorts. Gr ≥3 TRAEs occurred in 42–85%. Gr ≥3 keratopathy occurred in 0 patients in 1.9 mg/kg Q8W, 1 patient (25%) in 1.9 mg/kg Q4W, 8 patients (50%) in 2.5 mg/kg Q4W, and 6 patients (46%) in 2.5 mg/kg Q4W SPLIT cohorts. Image:Summary/Conclusion: Belamaf + LenDex had a tolerable safety profile, with no new safety signals identified in patients with RRMM. AEs, including keratopathy, were common but manageable with dose modifications. Encouraging clinical activity is observed with this combination in patients with RRMM. Follow-up/correlative studies are ongoing.
P567: CENTRAL NERVOUS SYSTEM INVOLVEMENT IN ADULT PATIENTS WITH ACUTE MYELOID LEUKEMIA – INCIDENCE AND OUTCOME
Authors: M. Virijevic, I. Djunic, M. Mitrovic, N. Pantic, Z. Pravdic, N. Sabljic, A. Novkovic, M. Cvetovic, J. Rajic, A. Vidovic, M. Todorovic-Balint, N. Suvajdzic-Vukovic
Journal: HemaSphere (2022)

Background: Examination of central nervous system (CNS) involvement is not routine diagnostic in adult patients with acute myeloid leukemia (AML). Therefore, its impact on the disease course is not well defined. There are studies showing that CNS involvement in AML is associated with a worse outcome, whereas others did not confirm such impact on long-term survival. Aims: To determine the incidence of CNS involvement, its impact on the disease free and overall survival, and to define risk factors for CNS involvement. Methods: This single center, retrospective study involved 645 adult patients with nonpromyelocytic AML, diagnosed in period of 2013. and 2021. In patients with the presence of CNS symptoms, with increased leukocyte count (≥30x109/L), FLT3 mutation, monocyte phenotype, CD56 positivity, a lumbar puncture was performed. All cerebrospinal fluid (CSF) samples were examined by flow cytometry (FCM). Treatment of CNS+ include intrathecal CT: cytarabine 100 mg. Assessment of remission of CNS+ was performed after 8 i.t. CT. The following parameters were estimated as risk factors for CNS+ at diagnosis of AML: age, WBC (<30x109/L vs. ≥30x109/L), ECOG PS, HCT CI score, elevated lactate dehydrogenase (LDH), leukemia-related parameters (cytogenetics (including ELN risk stratification), flow cytometry). The methods of descriptive and analytical statistics were used. Univariate and multivariate Cox Proportional Hazards models were used to identify risk factors. Results: CNS involvement examination was performed in 272 patietns. A total of 55/272 (20.2%) patients had proven CNS involvement, while 217/272 (79.8%) were without neuroleukemia. Complete remission was achieved by 168/272 (61.7%) of patients, but there was no statistically significant difference between CNS positive and CNS negative patients (p=0.619). Patients with CNS involvement at diagnosis had a significantly higher frequency of hyperleukocytosis (≥30x109/L), age ≤50 years, French–American–British M5 subtype, expression of CD56 and CD15 antigen. Multivariate analysis identified CD56+ as the most important risk factor for CNS+ at diagnosis in AML patients: p=0.003, HR 2.271; 95% confidental interval (CI)= 1.320-3.908. There were no statistically significant differences in 5-year overall survival and disease free survival between CNS positive and CNS negative patients. Summary/Conclusion: Our study showed a high incidence of CNS involvement in AML patients, compared to studies in which the incidence was significantly less (3.3%). Our study confirmed the accuracy of the factor we used to assess CNS involvement. There was no difference in the outcome between patients with CNS involvement and those without.
Association of Clinical and Demographic Characteristics With Response to Electroconvulsive Therapy in Mania
Authors: Katarzyna Popiolek, Susanne Bejerot, Mikael Landén, Axel Nordenskjöld
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Knowledge of the effectiveness of electroconvulsive therapy (ECT) in the treatment of manic episodes is based on clinical experience, but empirical evidence is scarce. Moreover, prognostic factors associated with response to ECT in patients with mania are poorly understood. <h3>Objective</h3> To investigate the response to ECT in patients with manic episodes. <h3>Design, Setting, and Participants</h3> This nationwide, register-based observational cohort study was conducted using data from patients admitted to psychiatric departments in Sweden that reported data to the Swedish National Quality Registry for ECT (Q-ECT). Patients admitted to any hospital in Sweden and receiving ECT for a manic episode between 2012 and 2019 were considered for inclusion (605 individuals). The outcome, Clinical Global Impression Improvement scale (CGI-I) score, was available in 571 patients. Data from several national registers were combined to determine clinical and sociodemographic factors. Analysis of data occurred from April through September 2021. <h3>Exposures</h3> Patients treated with ECT for a mania were identified from the Q-ECT. <h3>Main Outcomes and Measures</h3> Response to ECT was defined by a CGI-I score of 1 (very much improved) or 2 (much improved). Remission was defined as a Clinical Global Impression Severity scale (CGI-S) score of 1 (reference range or not ill) or 2 (minimally ill) within 1 week after ECT. Univariate and multivariable regression models were used to investigate associations of sociodemographic factors, psychopharmacology, and comorbidities with response. <h3>Results</h3> Among 571 patients with mania treated with ECT (211 [37.0%] men; median [IQR] age, 46 [31-59] years), 482 patients (84.4%) responded to ECT. Comorbid anxiety and obsessive-compulsive disorder (OCD) were associated with lower odds of response to ECT (adjusted odds ratio [aOR], 0.48; 95% CI, 0.25-0.90 and aOR, 0.17; 95% CI, 0.06-0.56, respectively). Patients who were markedly ill (aOR, 2.93; 95% CI, 1.23-7.00), severely ill (aOR, 2.60; 95% CI, 1.06-6.34), or among the most extremely ill (aOR, 7.94; 95% CI, 2.16-29.21) according to CGI-S score had higher odds of response than those with mild or moderate illness. <h3>Conclusions and Relevance</h3> This study found that ECT was associated with improvement for mania in clinical settings, with especially high response rates in patients with severe illness and those without comorbid anxiety or OCD.
P1168: CHARACTERISTICS PREDICTIVE OF PROGRESSION DURING FRONTLINE TREATMENT IN AGGRESSIVE B-CELL LYMPHOMAS
Authors: A. Bock, R. Mwangi, M. Maurer, J. Cerhan, W. L. Ng, R. King, N. N. Bennani, S. Ansell, T. Habermann, T. Witzig, Y. Wang, G. Nowakowski
Journal: HemaSphere (2022)

Background: Primary refractory diffuse large B-cell lymphoma (DLBCL) represents 10-15% of DLBCL cases. The subgroup of refractory patients who have no response or progressive disease (PD) by the end of frontline treatment (EOT) is a high-risk group with particularly poor outcomes. It is challenging to identify such patients at diagnosis. Aims: To identify clinical, pathological, and cytogenetic characteristics of patients with progression during frontline treatment. Methods: Adult patients with newly diagnosed DLBCL, including patients with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (DHL/THL), between 2002 and 2019 and seen at Mayo Clinic Rochester were identified from the prospective Molecular Epidemiology Resource (MER) cohort study of the University of Iowa/Mayo Clinic Lymphoma SPORE. We analyzed patients who had no response or PD during treatment or by EOT (early PD group) and compared to non-early PD (non-ePD) patients (including relapsed patients). We compared demographics, clinical characteristics, cell of origin (COO), and MYC rearrangements using Chi-square analysis. Results: Out of 1,505 patients with DLBCL, there were 66 patients (4.3%) with early PD (N=20 PD/stable disease at interim PET-CT, N=46 PD by EOT). At baseline, 61% were male and the median age was 60. Early PD patients had more advanced stage III-IV (72.7% vs 53.3%), elevated serum lactate dehydrogenase (LDH) (64.0% vs 47.3%), >1 extranodal site involved (36.4% vs 23.3%), and International Prognostic Index (IPI) ≥3 (52.0% vs 33.6%)(all p <0.05 compared to non-ePD). COO distribution was similar between early PD and non-ePD patients. Among patients with complete pathological and cytogenetic data available (early PD, n=47; non-ePD, n=813), DHL or THL was observed in 23.4% of early PD patients compared to 9.2% in non-ePD patients (p=0.001). Of the DHL patients in the early PD group (n=8), MYC/BCL2 rearrangement was present in 87.5%, MYC/BCL6 in 12.5%. Dual Myc/Bcl2 expressor (DEL) was present in 42.2% of early PD patients (n=45) compared to 25.5% in non-ePD patients (n=736)(p=0.013). First-line treatment regimens in the early PD group included R-CHOP (74.2%), R-EPOCH (7.6%), and other immunochemotherapy (IC)(18.2%), which was similar to non-ePD patients. Summary/Conclusion: High-risk characteristics including DHL/THL and DEL are significantly associated with progressive disease during frontline treatment, suggesting that MYC-signaling may mediate chemoresistance. Known high-risk clinical features including advanced stage, elevated LDH, >1 extranodal site, and IPI ≥3 are also associated with early PD. Early identification of patients at high risk for early PD through clinical, pathological, and cytogenetic features is of utmost importance given the availability of clinical trials incorporating novel therapies in both frontline and consolidative approaches.
S115: MUTANT NPM1 BINDS CHROMATIN AND COOPERATES WITH MLL1 TO REGULATE ONCOGENIC TRANSCRIPTION
Authors: H. Uckelmann, S. Armstrong, E. Haarer, E. Wong, C. Hatton, F. Perner, C. Marinaccio, C.-W. Chen
Journal: HemaSphere (2022)

Background: The dysregulation of stem cell and self-renewal associated genes is a common phenomenon during leukemia development. In acute myeloid leukemia (AML) around 50 % of cases express high levels of HOXA cluster genes and MEIS1. Most of these AML cases harbor an NPM1 mutation (NPM1c), which encodes for an oncogene that is mislocalized from the nucleolus to the cytoplasm. Hence, most studies of NPM1c have focused on a potential cytoplasmic role. However, it remains unclear how NPM1c expression in hematopoietic cells leads to its characteristic gene expression pattern. Furthermore, NPM1c AMLs are highly sensitive to the disruption of the MLL1 histone methyltransferase complex. Small molecule inhibitors that block the interaction between MLL1 and its adaptor protein Menin have been shown to impair binding of MLL1 to a subset of its target genes and to inhibit leukemia cell proliferation and self renewal. Several MLL1-Menin inhibitors are currently in Phase I/II clinical trials and show promising activity in patients with NPM1c AML. The effectiveness of these molecules in NPM1c AML prompts the question whether NPM1c and the wildtype MLL complex cooperate directly on chromatin to drive leukemic self-renewal. Aims: In this study we investigated the potential role of NPM1c in regulating oncogenic transcription on chromatin and the interplay between NPM1c and the histone methyltransferase complex KMT2A (MLL1). Methods: We used an endogenously degrader tagged NPM1c leukemia cell line that allows rapid small molecule induced degradation to show that NPM1c occupies specific chromatin targets in AML. To characterize the effects of NPM1c degradation on the chromatin landscape and transcriptional output at genomic loci that are bound by NPM1c we used ChIPseq, PROseq and nascent RNAseq methods. Results: Our results show that endogenous NPM1c directly binds to chromatin at specific target genes, such as HOXA9 and MEIS1, which are highly expressed in NPM1c patient samples. The loss of NPM1c from its targets leads to specific alterations in active chromatin marks and RNA Polymerase II (Pol II) chromatin occupancy which are accompanied by rapid changes in gene expression as well as Pol II transcriptional activity. The recruitment of NPM1c to chromatin is dependent on the nuclear exporter CRM1 as well as one of the acidic domains of NPM1c. We further show that NPM1c is lost from specific loci after treatment with small molecules that disrupt the MLL1-Menin complex interaction thus functionally linking targeted epigenetic therapy and NPM1c function. Summary/Conclusion: Overall, we demonstrate that NPM1c directly regulates a network of leukemia self-renewal associated genes through direct chromatin interaction. We further found that NPM1c acts in collaboration with the MLL1 complex and define the mechanism by which MLL1-Menin small molecule inhibitors produce clinical responses in patients with NPM1-mutated AML.
P1205: PROGNOSTIC ROLE OF TUMOR P53 MUTATION IN DIFFUSE LARGE B CELL LYMPHOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: J. Ma, H. Peng, Q. He, J. Shi
Journal: HemaSphere (2022)

Background: TP53 gene is the most commonly mutated gene in human cancers, and dysregulation of the TP53 pathway is essential in cancer pathogenesis, predominantly in diffuse large B-cell lymphoma (DLBCL). In 2011, Lenka Stefancikova first reported the effect of TP53 mutation (21.3%) and treatment sensitivity prognosis in DLBCL patients. A 2012 article in BLOOD showed that missense mutations in the DNA binding domain of the TP53 gene, rather than deletes or heterozygous deletes, lead to poorer survival in DLBCL patients. In 2017, Wang et al. found that patients with TP53 gene mutation had a worse prognosis than patients with double-hit / double expression. In the same year, Thorsten Zenz retrospectively analyzed TP53 subgroup data from the Recover-60 trial, and TP53 mutations were associated with reduced complete response, event-free, progression-free, and overall survival. Aims: We hope to find favorable evidence of whether P53 mutation affects diffuse large B lymphoma prognosis. Therefore, we conducted a systematic review and meta-analysis of P53 mutation rate, response rate, and prognostic significance in diffuse large B-cell tumors. Methods: A literature search was conducted on the prognosis of P53 mutation in diffuse large B-cell tumors in the PubMed database. Data on the efficacy and prognosis of P53 mutation in diffuse large B-cell tumor patients were extracted, and the associations between P53mutations and clinicopathologic parameters were examined. Hazard ratio (HR) and 95% confidence interval (CI) were calculated and combined using the random-effect Mantel-Haenszel model. The effect of P53 mutation on outcome parameters was estimated with a 95% confidence interval odds ratio. Results: Twenty studies with 2,704 patients were eligible for inclusion. The mutation rate of P53 in 19 studies was 21%. In 6 studies, the CR rate of P53 mutation patients was 36% (95% confidence interval 0.32-0.41); the total HR of CR was 0.39 (95% confidence interval 0.29-0.53). Data on overall survival (OS) and progression-free survival (PFS) were obtained from 16 and 8 studies. When comparing patients with P53 mutant DLBCL and P53 wild-type DLBCL, the total HR of OS and PFS were 2.26 (95% confidence interval 1.90-2.69) and 1.90 (95% confidence interval 1.49-2.42). Image:Summary/Conclusion: Our fundings suggest that P53 mutation shows negative associations with CR and harms OS and PFS prognosis. Clinical trials targeting TP53 mutations are needed to solve the problem.
PB2170: HIGH EXPRESSION OF AP2M1 CORRELATES WITH WORSE PROGNOSIS BY REGULATING IMMUNE MICROENVIRONMENT AND DRUG RESPONSE TO R-CHOP IN DLBCL
Authors: X.-D. Liu, Y.-Z. Liang, Y.-S. Piao, L. Wang
Journal: HemaSphere (2022)

Background: DLBCL (diffuse large B cell lymphoma) is the most common subtype of non-Hodgkin lymphoma (NHL). After anthracycline-based chemotherapy, more than 70% of DLBCL patients can get complete response or partial response, but only 50% - 60% of patients can survive for a long time. Adaptor Related Protein Complex 2 Subunit Mu 1 (AP2M1) encodes a subunit of the hetero tetrameric coat assembly protein complex 2 (AP2), which required for the activity of a vacuolar ATPase and may also play an important role in regulating the intracellular trafficking and function of CTLA-4 protein. There are few reports on the relationship between DLBCL and AP2M1. Meanwhile, it is unclear whether it is related to the pathogenesis of DLBCL. Aims: Here, in this study, the relationship between DLBCL and AP2M1 and its effect in DLBCL chemotherapy were studied. Methods: Using public datasets of DLBCL from both GEO and TCGA databases, we analyzed the role of AP2M1 in mediating chemoresistance to R-CHOP and its correlation with various clinical parameters and prognosis. By using various R packages, we evaluated the role of AP2M1 on regulating tumor immune microenvironment. Moreover, FFPE samples of DLBCL from Beijing Tongren Hospital were used to valiate our findings. Results: We found that the expression of AP2M1 was significantly increased in DLBCL, which was correlated with poor prognosis and a variety of clinical indicators. On the basis of enrichment analysis, it was found that AP2M1 may be related to intracellular receptor signaling pathway. Through immune analysis and drug prediction, we found that the expression of AP2M1 affected the immune environment and drug response of DLBCL, which further revealed the important role of AP2M1 in DLBCL. Using FFPE DLBCL samples from patients treated in our center, we validated the above findings that high expression of AP2M1 correlated with inferior survival outcomes and affected sensitivity to R-CHOP treatment. Image:Summary/Conclusion: In this study, we found that the expression of AP2M1 could affect the prognosis of DLBCL patients by affecting the immune environment, and the expression of AP2M1 affected the response of many drugs in DLBCL treatment, indicating AP2M1 as a potential therapy target in DLBCL.
PB1893: THE STUDY OF SET GENE AND PROTEIN PHOSPHATASE 2A IN CHRONIC MYELOID LEUKEMIA AND THEIR ROLE IN DISEASE PROGRESSION
Authors: H. Fathy, H. Naenaa, N. Halawani, A. Bassiouny, R. Abo Elwafa, N. Farrag
Journal: HemaSphere (2022)

Background: Chronic myeloid leukemia (CML) is characterized by three stages, chronic, accelerated and blastic phases. Tyrosine kinase inhibitors (TKIs) delay the progression of CML into blastic phase. However, resistance to TKIs has emerged due to different factors. Protein phosphatase 2A (PP2A) is a tumor suppressor protein that affect many cellular pathways. Inhibition of PP2A by PP2A inhibitors such as SET is one mechanism responsible for CML progression. Moreover, phosphorylation of C-terminal tyrosine residue (Tyr307) on the PP2A catalytic subunit was associated with decreased protein activity and consequently, loss of its tumor suppression function. Aims: This work studied the role of SET gene expression as well as phosphorylated PP2A expression in CML progression Methods: The study included 50 CML patients under TKI therapy for at least 18 months, and 50 healthy controls. All study participants were tested for SET gene expression level in peripheral blood by RQ-PCR and PP2A (Tyr307) in serum by ELISA. Moreover, patients were analyzed for complete blood count, BCR-ABL1 in peripheral blood by RQ-PCR and bone marrow examination. Results: High SET gene expression in patients was found to be significantly associated with advanced disease phase and worse clinical and laboratory findings while low expression was significantly associated with better molecular response assessed by BCR-ABL1 level. High levels of PP2A (Tyr307) was significantly associated with blastic phase. Moreover, significant positive correlations was found between BCR-ABL1 level and both SET gene expression and PP2A Tyr307 levels. Image:Summary/Conclusion: SET gene and PP2A are important factors in CML progression and can be used as possible targets for treatment in TKI-resistant cases.